The long term objective is a better understanding of inherent protective mechanisms that control acute airway responses to inhaled stimuli. The focus is on two specific aspects of control, both of which serve to protect against excessive or unabated bronchoconstriction; by promoting bronchodilatation. These include: (1) the regulation of bronchomotor tone by lung inflation; and (2) the regulation of airway tone by a unique intrinsic bronchodilator mechanism stimulated by Prostaglandin (PG) F2 alpha. This research is based on the premise that a defect in either of these regulatory functions may lead to exaggerated states of airway reactivity, or airway hyperresponsiveness.
The specific aims of the project will be pursued at the in vivo level in human bronchial challenge experiments and at the in vitro level in studies of guinea pig and human airway tissue. Specific studies related to volume regulation of bronchomotor tone will be carried out with the aim of establishing (1) the role of an impaired capacity to dilate airways by lung inflation in the evolution of abnormal airway responsiveness after allergen-induced airway inflammation; (2) the mechanisms whereby allergen-induced airway inflammation alters the dilator effects of lung inflation and airway responsiveness; (3) the effects of anti-inflammatory agents in preventing allergen-induced abnormalities in the volume regulation of bronchomotor tone and airway responsiveness; (4) the role of volume regulation in determining the shape of methacholine dose-response curves in asthmatic subjects; and (5) the importance of abnormal lung recoil pressures as a cause of impaired volume regulation of bronchomotor tone. Studies of the airway physiology and pharmacology of PGF2 alpha will be carried out to (1) explain why atopy is associated with airway hyperresponsiveness to PGF2 alpha but to other chemical stimuli: (2) define the characteristics of the novel bronchodilator effects of PGF2 alpha in man; (3) establish the relation between a defect in the bronchodilator effects of PGF2 alpha and airway hyperresponsiveness; (4) define the importance of PGF2 alpha-induced bronchodilatation in modulating airway responses to clinically relevant bronchoactive stimuli; and (5) define the mechanisms and characteristics of the bronchodilator effects of PGF2 alpha in isolated guinea pig and human airway tissue. This work is expected to contribute significant new information toward a better understanding of the mechanisms involved in pathologic airway responsiveness, and to lead to the development of more rational approaches to effective therapy of diseases characterized by airway dysfunction.
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